Disseminated infection (mycobacteremia) with Mycobacterium tuberculosis (dMTB) has been documented by our group in 10-25 percent of patients with HIV infection in Africa using lysis- centrifugation blood cultures. Unlike pulmonary tuberculosis (pMTB), most cases of dMTB are not recognized and death ensues rapidly. Thus, in developing countries dMTB may be a more important cause of HIV-associated mortality than pMTB. Risk factors for dMTB have not been identified and it is not known if most cases are due to primary infection, reactivation or re- infection. We hypothesize that most cases of dMTB are due to primary MTB infection in patients without prior infection with MTB or non-tuberculous mycobacteria (NTM). Mycobacterial immunization in early HIV infection is a potential strategy to prevent dMTB. Mycobacterium vaccae (MV) is an investigational vaccine prepared by heat inactivation of an NTM, and has been shown to be protective against MTB in several animal models. Studies conducted by our group indicate that a 5-dose series of MV is safe in patients with HIV infection and induces a durable cellular immune response to MTB antigens in persons with prior BCG immunization. Our hypothesis is that MV immunization will reduce the risk of HIV-associated dMTB by 50 percent. Our specific aims are: (1) to define risk factors for HIV-associated disseminated tuberculosis and to assess the relative contributions of primary infection, reactivation and re-infection in the pathogenesis of disseminated tuberculosis, and (2) to assess the safety and efficacy of a 5-dose schedule of inactivated MV vaccine for the prevention of HIV-associated pulmonary and disseminated tuberculosis in persons with prior BCG immunization. 2274 HIV-positive patients with prior BCG immunization and 100 HIV-negative controls will be entered in a 5-year study in Zambia. Baseline evaluation will include history, chest x-ray, dual skin tests with purified protein derivative (PPD) and Mycobacterium avium sensitin (MAS), and whole blood assay for interferon-gamma production in response to MV sonicate, PPD, ESAT-6 (a protein antigen unique to MTB) and MTB antigen 85. Subjects with PPD reactions greater than or equal to 5 mm will receive 6 months of prophylaxis with isoniazid. All subjects will be randomized 1:1 to receive a 5-dose series of MV or placebo over 12 months with repeat skin test and in vitro studies at 14 months. Subjects will be followed every 3 months for 3-5 years to assess new pMTB (microbiologic or clinical diagnosis) or dMTB (microbiologic diagnosis). All isolates will have susceptibility tests and IS6110 DNA fingerprinting performed. Potential risk factors for dMTB, including baseline PPD test results, will be assessed in placebo and vaccine groups. Vaccine efficacy against dMTB and pMTB in HIV-positive subjects will be determined, and post immunization interferon gamma responses used to identify a surrogate marker of efficacy. The proposed study has important implications for the reduction in mortality from HIV-associated tuberculosis and for design of future trials of new vaccines against tuberculosis.